This is an application for a K23 award for Dr. Angela Rogers, a pulmonary critical care physician at Stanford University. Dr. Rogers is establishing herself as a young investigator in the field of Acute Respiratory Distress Syndrome (ARDS) genomics, with a focus on using cutting-edge genomics techniques to identify novel biology in ARDS. This K23 award period will provide Dr. Rogers with critical support to achieve the following goals: 1) to develop expertise in ARDS phenotyping, cohort development, and clinical trials by working closely with her Primary Mentor, Dr. Michael Matthay; 2) to learn key skills in metabolomics and network analysis by pursuing advanced training and working with Stanford-based co-Mentors and Advisors; and 3) to develop an independent research career. To successfully meet these goals, Dr. Rogers has assembled a highly collaborative and committed group of Mentors and co-Mentors. Her Primary Mentor, Dr. Michael Matthay from UCSF, is a world expert in the science of ARDS pathogenesis and is already serving as Dr. Rogers's Primary Mentor for her Parker B. Francis award. Co-Mentors Dr. Mark Nicolls, the Chief of Pulmonary and Critical Care Medicine at Stanford Division, is an expert in translational science and leads the K12 in 'omics of lung diseases at Stanford, and co-Mentor Dr. Euan Ashley is a Stanford cardiologist and Associate Professor with a lab focus on network medicine analytic approaches. Dr. Rogers has assembled key Scientific Advisors (including Dr. Gary Peltz, a Stanford Professor of Anesthesia with expertise in metabolomics), who will additionally advise her on key aspects of this proposal. ARDS is a common cause of acute respiratory failure that occurs in a subset of patients who develop critical illness. Despite recent advances in ARDS management, development of ARDS carries substantial upfront mortality and long-term morbidity among survivors. Dr. Rogers's long-term career goal is to use genomics to identify high-risk populations and to define novel ARDS biology. The goal of this proposal is to study metabolomics (the chemical products of cellular metabolism) in the plasma of critically ill patients who are at risk for ARDS. Metabolic derangements have never been studied in patients who are at high risk for ARDS, yet have high potential to identify novel biology. In this work, she will perform targeted metabolomic profiling focused on 2 pathways: free fatty acids (FFA, AIM 1) and oxidative phosphorylation (AIM 2), based on her preliminary data that both are altered in established ARDS. Metabolic changes will be tested for association with ARDS development both individually and as part of metabolic networks (AIM 3). To provide greater mechanistic insight, networks will additionally be compared to known protein biomarkers as an intermediate phenotype in ARDS (AIM 3B). Initial metabolomic profiling will utilize the existing EARLI (Early and Assessment of Renal and Lung Injury) cohort from UCSF. After technical validation, we will replicate top metabolomic associations in a Stanford ICU population that Dr. Rogers will recruit and phenotype throughout this K23 period. We anticipate that we will identify plasma FFA and oxidative phosphorylation metabolites that are altered in patients who develop ARDS. Such metabolic derangements could both serve as biomarkers to facilitate enrollment into emerging clinical trials, and define novel biology in ARDS pathogenesis. Thus, the work proposed here has excellent potential to translate into clinically actionable results for critically ill patients This research will form the basis for an R01-level application to study the association between untargeted metabolomic derangements and development of ARDS in high risk critically ill patients. In leading the work proposed here, Dr. Rogers will gain critical experience and formal training in ICU phenotyping, metabolomics, and network analysis needed to transition to an independent career as a translational scientist.